Silver-Containing Antimicrobial Articles and Methods of Manufacture

ABSTRACT

A silver composition comprising silver sulfate, methods of making antimicrobial articles, particularly packaged antimicrobial articles, methods of whitening antimicrobial articles, and packaged antimicrobial articles.

BACKGROUND

While wounds heal more effectively in moist environments, bacterialinfection poses increased risk. Use of antibiotics to treat bacterialinfections can build bacterial resistance. Silver compounds are known toimpart antimicrobial effects to a surface with minimal risk ofdeveloping bacterial resistance. Silver is delivered to the surface bysustained release of silver ions from the surface when in contact withmoist environments, such as a wound bed.

Silver compositions, such as silver nitrate and silver sulfadiazine, areeffective antimicrobials used in a variety of applications. However,they are typically not light stable, leave a stain on skin with whichthey come into contact, and in the case of silver nitrate, can bequickly depleted in an aqueous environment. Use of silver salts asantimicrobials have included the use of stabilizing agents to increaselight stability such as those described in U.S. Pat. No. 2,791,518(Stokes et al.) (using a first solution of ammonia, silver nitrate andbarium nitrate; and a second solution of sodium chloride and sodiumsulfate); and in U.S. Pat. No. 6,669,981 (Parsons et al.) (a silver saltin water/organic solvent followed by one or more stabilizing agents(e.g., ammonium salts, thiosulphates, chlorides and/or peroxides)).

SUMMARY

The present invention is directed to methods of making antimicrobialarticles, particularly packaged antimicrobial articles, methods ofwhitening antimicrobial articles, and packaged antimicrobial articles.

In one embodiment, the present invention provides a method of making apackaged antimicrobial article. The method includes: preparing acomposition comprising silver sulfate; coating the silver sulfatecomposition on a substrate; drying the coated substrate to form anantimicrobial article; placing the antimicrobial article in packagingmaterial having a volatile organic content of no greater than 100 mg persquare meter, and sealing the packaging material with the antimicrobialarticle therein.

In another embodiment, the present invention provides a method ofwhitening at least a portion of an antimicrobial article. The methodincludes: providing a packaged antimicrobial article having at least aportion colored other than white, wherein the article includes asubstrate coated with a silver salt composition including at least aportion of the silver in the zero-valent state, and wherein theantimicrobial article is sealed within packaging material having avolatile organic content of greater than 100 milligrams per square meter(100 mg/m²); and irradiating the packaged antimicrobial article towhiten at least a portion of the antimicrobial article.

In other embodiments, the present invention provides packagedantimicrobial articles. In one embodiment, a packaged antimicrobialarticle includes: an antimicrobial article including a substrate coatedwith a silver sulfate composition; and packaging having theantimicrobial article sealed therein; wherein the packaging comprisesmaterial having a volatile organic content of no greater than 100 mg/m².

In certain preferred embodiments of the present invention, antimicrobialarticles are color stable, particularly during and/or after irradiation.In this context, “color stable” means that the color of the dried silversulfate composition coated on a substrate does not exhibit a significantchange in color and/or color homogeneity to the human eye over time(preferably at least 4 hours, more preferably at least 8 hours, evenmore preferably at least 48 hours, and even more preferably at least 1week) when compared to the same coated composition on a substrate thathas not been exposed to light (e.g., fluorescent, natural, UV).Preferably, “color stable” means that the color of the dried silversulfate composition coated on a substrate does not exhibit a perceptiblechange to the human eye over time (preferably at least 4 hours, morepreferably at least 8 hours, even more preferably at least 48 hours, andeven more preferably at least 1 week) when compared to the same coatedcomposition on a substrate that has not been exposed to light (e.g.,fluorescent, natural, UV).

Color change can be evaluated in a number of ways using a number ofgrading scales. For example, color change can be evaluated by visualranking under fluorescent lighting. Samples are compared to colorstandards and given a rating based on that visual comparison. In thisranking scale, 0, 1, and 2 are classified as “whitish” including whiteto cream, 3 through 5 are classified as “yellowish” including lightyellow to golden yellow, and 6 through 10 are classified as rust to darkbrown. Color change is the difference in ratings obtained by subtractingthe initial rating from the rating after treatment. Positive ratingsrepresent a darkening in appearance and negative ratings represent alightening in appearance. A color change on this scale of 1 or less isacceptable as long as the color is substantially homogeneous. If thecolor is non-homogeneous, even a color change of 0.5 is considered a“significant” and unacceptable change.

Color change can also be measured using a colorimeter such as a MinoltaChroma Meter (CR-300, manufactured by Konica Minolta Photo ImagingU.S.A., Inc., Mahwah, N.J.) using tristimulus values. A color change onthis scale in the “Y” value of 15% or less is acceptable as long as thecolor is homogeneous. If the color is non-homogeneous, even a colorchange of 5% in the “Y” value is considered a “significant” andunacceptable change.

Color change can also be measured using a calorimeter according to ASTMD2244. The resulting CIELAB color difference (DE*), between the sampleafter exposure for the indicated period of time and the unexposed samplecan be determined. For purposes of reference only, a DE*, or colorchange of about 2 units is just detectable by the naked eye whereas aDE* of 20 or greater represents a substantial or “significant” andunacceptable color change.

In certain preferred embodiments of the present invention, antimicrobialarticles are maintained in an environment of no more than 50% RH (i.e.,a water activity of 0.5) at room temperature. In certain preferredembodiments of the present invention, antimicrobial articles aremaintained in an environment of no more than 30% RH at room temperature.In this context “room temperature” means an average room temperature,typically 23° C.+/−2° C. “Relative humidity” the ratio of the quantityof water vapor present in the atmosphere to the quantity that wouldsaturate the atmosphere at the given temperature.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably. Also herein, the recitations of numerical rangesby endpoints include all numbers subsumed within that range (e.g., 1 to5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

The terms “comprises” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

The words “preferred” and “preferably” refer to embodiments of theinvention that may afford certain benefits, under certain circumstances.However, other embodiments may also be preferred, under the same orother circumstances. Furthermore, the recitation of one or morepreferred embodiments does not imply that other embodiments are notuseful, and is not intended to exclude other embodiments from the scopeof the invention.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

The present invention is directed to methods of making antimicrobialarticles, particularly packaged antimicrobial articles, methods ofwhitening antimicrobial articles, and packaged antimicrobial articles.

In certain embodiments, the antimicrobial articles are prepared using acomposition including silver sulfate (e.g., an aqueous-basedcomposition), coating the silver sulfate composition on a substrate, anddrying the coated substrate to form an antimicrobial article. Theantimicrobial article is placed in packaging material and the packagingmaterial sealed with the antimicrobial article therein. Accordingly, thepresent invention provides a packaged antimicrobial article thatincludes an antimicrobial article that includes a substrate coated witha silver sulfate composition, and packaging having the antimicrobialarticle sealed therein. In certain embodiments, the antimicrobialarticle sealed in the packaging material is irradiated.

In certain embodiments, the packaging includes material having avolatile organic content of no greater than 100 milligrams per squaremeter (mg/m²). In other embodiments, the volatile organic content is nogreater than 50 mg per square meter. In this context, the “volatileorganic content” is defined by the equation: (mass of packaging materialbefore oven exposure−mass of packaging material after ovenexposure)/surface area. This can be determined using ASTM D 2369-03 asdescribed in the Examples Section.

Useful packaging materials for the present invention may be porous ornonporous, as long as it maintains sterility of the product aftersterilization. Useful packages may include one or more layers ofmaterials. There may be one or more packages surrounding a substrate.For example, there may be one or more inner pouches within an outerpouch. In such a situation, the innermost pouch (i.e., the one in directcontact with the antimicrobial article) is preferably porous. Sufficientporosity can allow for transfer of gases released during irradiation ofthe packaged antimicrobial article. Typically, in such a situation wherethe innermost pouch is porous, the outermost pouch of the packagingmaterial is nonporous or of very low porosity, particularly with respectto oxygen permeability and moisture vapor permeability.

In certain embodiments, the packaging includes material having an oxygenpermeability of less than 0.01 cubic centimeter per 645 squarecentimeters per 24 hours. In this context, “oxygen permeability” isdefined as the volume of oxygen gas that diffuses through 645 squarecentimeters (100 square inches) of packaging film during 24 hours. Thiscan be determined using ASTM D3985.

In certain embodiments, the packaging includes material having amoisture vapor transmission rate (MVTR) of less than 0.01 gram per 645square centimeters per 24 hours. In this context, the MVTR is the massof water that diffuses through 645 square centimeters (100 squareinches) of packaging film during 24 hours. This can be determined usingASTM F1249.

Packaging materials having such properties include TPC-0765B/TPC-0760Bconstruction (Tolas Health Care; Feasterville, Pa.) and Techni-Pouchpackage (Technipaq, Inc., Crystal Lake, Ill.) with a PET(polyester)/Aluminum Foil/LLDPE (linear low density polyethylene)material construction.

In certain embodiments, the packaging includes a porous material havinga Gurley Hill porosity of less than 100 seconds per 100 cubiccentimeters of air (100 s/100 cc air). In certain embodiments, theporosity is at least 5 seconds per 100 cubic centimeters of air. Porouspackaging materials having this property include those commerciallyavailable under the tradename TYVEK such as TYVEK 1073B/TPF-0501A (aTYVEK/film construction) available from Tolas Health Care Packaging,Feasterville, Pa.; and paper/film type packaging construction such asthat available under the tradename CONVERTERS Sterilization Pouches(e.g., 3 inch×8 inch (7.5 cm×20 cm) size; Catalog 90308) distributed byCardinal Health of McGaw Park, Ill.

In certain embodiments, the packaging material includes an inner pouchand an outer pouch, wherein the inner pouch has a Gurley Hill porosityof less than 100 s/100 cc of air (preferably of 5 s to 100 s/100 cc ofair), and the outer pouch has an oxygen permeability of less than 0.01cubic centimeter per 645 square centimeters per 24 hours and/or amoisture vapor transmission rate of less than 0.01 gram per 645 squarecentimeters per 24 hours.

In certain embodiments, an antimicrobial article is made by dissolvingsilver sulfate in an aqueous-based composition, coating the compositionon a substrate, and drying the coated substrate. In certain embodiments,the substrate coated with silver sulfate remains stable to light (e.g.,visible, UV) and heat without the addition of traditional stabilizingagents such as ammonia, ammonium salts (e.g., ammonium acetate, ammoniumsulfate, and ammonium carbonate), thiosulfates, water insoluble salts ofmetals (e.g., halides such as chlorides), peroxides, magnesiumtrisilicate, and/or polymers.

Preferably, any component that would function as a stabilizing agent ispresent in amounts less than 100 parts per million (ppm), morepreferably less than 50 ppm, most preferably less than 20 ppm, based onthe total weight of the silver sulfate composition.

Alternatively, any component that would function as a stabilizing agentis present in amounts less than 1000 ppm, more preferably less than 500ppm, most preferably less than 100 ppm, based on the total weight of theantimicrobial article comprising a dried silver sulfate compositioncoated on a substrate.

The resultant solution containing the silver sulfate solution can becoated on a substrate, preferably an absorbent substrate, althoughnonabsorbent substrates can also be used. The coated substrate is driedto drive off the volatile components, such as water and organic solvents(e.g., methanol, ethanol, isopropanol, acetone, or other organicsolvents that are miscible with water). Drying can be accomplished atroom temperature or by heating the coated substrate. Heat will speed thedrying process. In a preferred embodiment, the coated substrate is driedat temperatures below 190° C., more preferably below 170° C., even morepreferably below 140° C., to minimize reduction of the silver compounds,and also prevent the oxidation of a cellulosic material, when used as asubstrate.

Further, tensile strength of an oxidizable substrate (such as cotton) ismaximized when the silver sulfate composition on the substrate is driedat a low temperature, preferably less that 140° C., more preferable atless than 100° C., and most preferably at less than 70° C.

Once dried, the substrate remains coated with the silver sulfate. Thecoated composition typically contains silver sulfate in a major amount.Low levels of silver metal (i.e., zero-valent silver) may be present inamounts, preferably less than 20 wt %, and more preferably, less than 10wt %, based on the total weight of the silver components in thecomposition. In some embodiments, the choice of starting materials anddrying temperatures results in a coating that leaves no residue withessentially only the silver sulfate remaining on the substrate, and allother components of the silver solution removed from the substrate upondrying.

When applied, the silver sulfate solution penetrates and impregnates theinterior of the substrate. For example, when gauze is used, the silversolution impregnates between the fibers of the gauze.

The concentration of silver sulfate on the substrate is a function ofthe amount of silver sulfate in solution, the total amount of solutionapplied onto a unit area of the substrate, and the drying temperature.The silver sulfate concentration on the substrate is typically less than30 mg/cm², and in certain embodiments less than 5 mg/cm². In a preferredembodiment, the silver sulfate concentration on the substrate rangesfrom 0.001 mg/cm² to 5 mg/cm², and in certain embodiments from 0.001mg/cm² to 1 mg/cm².

The substrate can be a woven or nonwoven material (e.g., a gauze) madeof natural or synthetic compounds. The substrate can be a porous ornonporous film. It can be a knitted fabric, a foam, or a hydrocolloid,for example.

In certain embodiments, the substrate is a silver nitrate oxidizablesubstrate. In certain embodiments, the substrate includes a cellulosicmaterial. Examples of cellulosic materials include polysaccharides ormodified polysaccharides, regenerated cellulose (such as rayon), paper,cotton, those materials available under the tradename TENCEL,carboxymethyl cellulose, and the like.

Other materials may be used, including for example,polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl ether, polyacrylate,polyacrylamide, collagen, gelatin, may be used. Non-absorbent substratesmay also be used including, but not limited to, nylon, polyester,polyethylene, and polypropylene.

Other suitable materials for the substrate include polyacrylonitrile,polyvinylidene difluoride, polytetrafluoroethylene, polyoxymethylene,polyvinyl chloride, polycarbonate, styrene-ethylenebutylene-styreneelastomer, styrene-butylene-styrene elastomer, styrene-isoprene-styreneelastomer, and combinations thereof. Other substrate materials aredisclosed herein below. Various combinations of materials may beincluded within the substrate. In certain embodiments, the substrateincludes a material selected from the group consisting of a cellulosicmaterial, nylon, polyester fiber, and combinations thereof. In certainembodiments, the substrate includes a cellulosic material. In certainembodiments, the cellulosic substrate includes cotton.

The method provides a silver sulfate solution for coating on a substratewithout using an acid. The presence of acid can hydrolyze the cellulosicmaterial. This aspect of the process allows the coating to be appliedwithout weakening the cellulosic substrate. Preferably the coatingsolution has a pH of at least 4, more preferably at least 5. Preferably,the coating solution has a pH of no greater than 9.

Elevated temperatures can also accelerate the oxidation of cellulose bya silver salt, resulting in such affects as lowering the tensilestrength and changing the color of the silver sulfate composition on thesubstrate. The color change on a cellulosic material, such as cotton, islikely due to the reduction of silver salt to silver metal with anaccompanying oxidation of the cellulose substrate. The oxidized cottonhas lower tensile strength.

If silver sulfate is coated on a cellulosic substrate or other easilyoxidizable substrate (e.g., a silver nitrate oxidizable substrate), thearticle will change color in proportion to the drying temperature andthe time in the drying device, such as an oven. Generally, no colorchange is observed when the substrate coated with the silver sulfatecomposition is dried below approximately 100° C. for 15 minutes. Forexample, when wetted cotton is dried at an oven temperature greater thanapproximately 100° C., the cotton substrate darkens in proportion to theoven temperature and turns yellow then brown then dark brown.

If a synthetic substrate such as polyester, which is not easilyoxidized, is coated with silver sulfate coating solution and dried, thepolyester will remain white even when dried at temperature above 100° C.Similarly, when polyester or other substrate material such as polyester,nylon, polyethylene, polypropylene, polyvinylidene difluoride,polytetrafluoroethylene, polyoxymethylene, polyvinyl chloride,polycarbonate, styrene-ethylenebutylene-styrene elastomer,styrene-butylene-styrene elastomer, or styrene-isoprene-styreneelastomer, is irradiated after being coated with silver sulfate coatingsolution and dried, the material does not typically change color.

The silver compositions, once coated, are preferably color stable (i.e.,stable to light as defined herein). In addition, preferably thecompositions are also stable to at least one of the following: heatand/or moisture. Regardless of substrate choice, preferably the coatedsilver sulfate composition is color stable. The initial color that thesilver sulfate solution develops after drying at a particulartemperature will remain without appreciable change over time (e.g.,preferably at least 4 hours, more preferably at least 8 hours, even morepreferably at least 48 hours, and even more preferably at least 1 week)either with or without exposure to light.

In certain situations, however, coated silver sulfate will change color.For example, in certain situations, irradiating an antimicrobial articleafter the article is placed in packaging and the packaging material issealed will cause a color change. This often occurs when the substrateof the antimicrobial article includes a cellulosic material. Theradiation typically includes gamma radiation and/or electron beamradiation. Such radiation is typically used to sterilize theantimicrobial articles. Thus, typical radiation levels include thatwhich is necessary to assure a Sterility Assurance Level of 10⁻⁶, basedon the AAMI Method of Sterility Assurance.

It has been discovered that this color change upon irradiation can occurin certain situations in standard packaging with a relatively highvolatile organic content (i.e., one with a volatile organic content(VOC) of greater than 100 mg/m²). Examples of such standard packaginginclude that available from Phoenix Healthcare Products, LLC, Milwaukee,Wis., and VP Group, Feuchtwangen, Germany. The use of packaging materialhaving a volatile organic content of no greater than 100 mg/m² asdescribed herein, however, in certain situations will reduce, and ofteneliminate, such a radiation-induced color change.

Low VOC packaging can be particularly useful when the color of thearticle is changed from the initial color (e.g., whitish) to a yellowishcolor, or some color other than a whitish color. Heat can cause a colorchange to a state that is more stable to irradiation than the initialcolor. For example, a silver sulfate composition that is dried to awhitish state will darken when irradiated in packaging regardless of thevolatile organic content; however, when it is heated to a temperaturethat causes the color to change to yellowish, this state is generallymore stable to irradiation and will typically not change color whenirradiated in a low VOC package (i.e., one with no greater than 100gm/m² VOC), particularly when low humidity conditions are used topackage the article, although it will in a high VOC package (unlesslarge amounts of substrate material are used relative to the amount ofpackaging material). For certain embodiments, the present inventionprovides a method of making a packaged antimicrobial article thatincludes drying the coated substrate at a temperature that causes thesilver sulfate composition to develop a yellowish color (typically dueto the formation of silver in the zero valence state during drying),which is color stable during and/or after irradiation (typically, afterirradiation, and preferably during and after irradiation). This isparticularly true for yellowish articles in low VOC packaging (i.e., nogreater than 100 gm/m² VOC) during and after e-beam irradiation, or withyellowish articles in low VOC packaging after gamma irradiation(although there may be a color change during gamma irradiation), or withyellowish articles in low VOC packaging during and after gammairradiation when low humidity packaging conditions are used (e.g., 30%RH or lower).

Whitish articles are not necessarily as color stable as yellowisharticles under similar conditions; however, whitish articles can becolor stable in low VOC packaging with activated carbon in thepackaging, particularly after e-beam or gamma irradiation. Thus, thepresent invention provides a method of making a packaged antimicrobialarticle that includes: preparing a composition including silver sulfate;coating the silver sulfate composition on a substrate; drying the coatedsubstrate occurs at a temperature that causes the silver sulfatecomposition to develop a whitish color; placing the antimicrobialarticle in packaging material having a volatile organic content of nogreater than 100 mg per square meter; and sealing the packaging materialwith the antimicrobial article therein; wherein activated carbon ispresent in the packaging, and further wherein the antimicrobial articleis color stable during and after irradiation.

Low VOC packaging, however, is not necessarily required with a yellowisharticle when the amount of substrate of the article is greater than 2 mgper interior square centimeter of packaging material. Thus, the presentinvention provides a color stable packaged antimicrobial article (and amethod of making) that includes: an antimicrobial article including asubstrate coated with a silver sulfate composition; and packaging havingthe antimicrobial article sealed therein; wherein the packaging includesmaterial having a volatile organic content of greater than 100 mg persquare meter; and wherein the ratio of antimicrobial article substrateto packaging material is greater than 2 mg substrate per interior squarecentimeter packaging material. The dried coated substrate includessilver in the zero-valent state, has a yellowish color, and preferablyis color stable after irradiation.

The color stability of the coated silver sulfate composition providesseveral advantages. The color stability provides an indication to theend user that the product is of consistent high quality. Further, thecolor stability indicates that the form of silver on the substrate hasnot appreciably changed which indicates that its performance (i.e.,silver release, antimicrobial activity) is essentially constant overtime in the package (e.g., preferably, at least 1 month, more preferablyat least 2 months, even more preferably at least 6 months, and even morepreferably at least 1 year). Thus, the use of packaging as describedherein is desirable when antimicrobial articles of the present inventionare irradiated and such color stability is desirable.

Such compositions are useful in medical articles, particularly wounddressings and wound packing materials, although a wide variety of otherproducts can be coated with the silver sulfate compositions.

Stability of the silver sulfate coated substrate is prolonged and/orincreased when the relative humidity (RH) at room temperature(particularly during the packaging process) is maintained at 50% orlower; more preferably at 30% or lower; and most preferably at 20% orlower. Relative humidity can be reduced to 30%, and preferably to 20%,or lower, for the silver sulfate coated substrate by a number of methodsincluding: 1) placing the coated substrate in an environment that has arelative humidity of 30% or lower, and preferably 20% or lower, and thenpackaging the product in the same environment; 2) drying the mesh in anoven, then immediately packaging the mesh; and 3) addition of adesiccant within the package. Preferably, to maintain a low relativehumidity in the dried silver sulfate composition, the article should bepackaged in a package with a low moisture vapor transmission rate (MVTR)such as a Techni-Pouch package (Technipaq, Inc., Crystal Lake, Ill.)with a PET/Aluminum Foil/LLDPE material construction. Low relativehumidity increases the thermal stability of silver sulfate treatedcotton.

In certain situations, it may be desirable to take advantage of thecolor change irradiation (e.g., gamma radiation and/or electron beamradiation) can cause in packaging with a volatile organic content ofgreater than 100 mg/m². Thus, the present invention also provides amethod of whitening at least a portion of an antimicrobial article. Forexample, if an antimicrobial article has at least a portion coloredother than whitish, wherein the article includes a substrate coated witha silver salt composition including at least a portion of the silver inthe zero-valent state, irradiating can whiten the colored portion.

Silver compounds, including silver sulfate, provide sustained release ofsilver ions over time based in part on their limited solubility andinherent dissociation equilibrium constants. The silver sulfatecomposition may have other silver salts, including those that are notcolor stable, in varying amounts, as long as the composition when coatedon the substrate remains color stable. In addition to silver sulfate,other silver compounds that may be coated on a substrate in addition tothe silver sulfate include silver oxide, silver acetate, silver nitrate,silver citrate, silver chloride, silver lactate, silver phosphate,silver stearate, silver thiocyanate, silver carbonate, silversaccharinate, silver anthranilate, silver benzoate, and combinationsthereof. Silver metal may also be present on the substrate. Preferably,the amount of silver compounds other than silver sulfate is less than 20wt %, more preferably less than 10 wt %, based on the total weightpercentage (wt %) of the silver components in the silver sulfatecomposition coated on the substrate.

The silver sulfate coated substrate remains stable when it containssilver sulfate in combination with other silver salts with limited colorstability. Preferably, the amount of silver sulfate is at least 60 wt %,more preferably at least 75 wt %, and most preferably at least 90 wt %,based on the total weight percentage (wt %) of the silver components inthe silver sulfate composition coated on the substrate.

Articles can be prepared using the silver solution described hereinaccording to a variety of coating methods. When a porous substrate iscoated, the process used typically allows the yarns, filaments, or filmsuch as perforated or microporous film, to be coated, while leaving mostof the apertures unobstructed by the composition. Depending on thestructure of the support used, the amount of solution employed will varyover a wide range.

The silver sulfate coating solution can be prepared by mixing silversulfate and distilled water. The silver sulfate coating solution canhave a range of concentrations up to a water solubility of about 0.6% atroom temperature. Optionally, higher concentrations of silver sulfatecan be obtained by dissolving silver sulfate in hot water. Optionallysulfate in other forms may be added, such as sodium sulfate.

The process can be accomplished as a continuous process, or it can bedone in a single step or with a single coating solution. The process toapply the coating does not require elevated temperatures, and can beapplied at temperatures less than 70° C. The coating solution can bemaintained below a pH of 9, and preferably less than 7, to minimizeadverse effects to the substrate. The coating solution can be maintainedat a pH above 4.

According to a variant of this process, a substrate can be passedthrough a bath of the silver composition. The substrate covered with thesilver sulfate composition is then dried, for example in an oven at atemperature sufficient to evaporate constituents of the solution. Thetemperature is preferably less than 190° C., more preferably less than170° C., and most preferably less than 140° C.

The silver sulfate solution can also be coated onto a carrier web or abacking (described below) using a known coating technique such asgravure coating, curtain coating, die coating, knife coating, rollcoating, or spray coating. A preferred coating method is gravurecoating.

Medical Articles

The silver compositions of the present invention can be used in a widevariety of products, although they are preferably used in medicalarticles. Such medical articles can be in the form of a wound dressing,wound packing material, or other material that is applied directly to orcontacts a wound. Other potential products include clothing, bedding,masks, dust cloths, shoe inserts, diapers, and hospital materials suchas blankets, surgical drapes and gowns.

The silver compositions can be coated on various backings (i.e., asupport substrate). The backing or support substrate can be porous ornonporous. The composition of the present invention can be coated on thesupport substrate or impregnated into it, for example.

Suitable materials are preferably flexible, and may be fabric, non-wovenor woven polymeric webs, polymer films, hydrocolloids, foam, metallicfoils, paper, and/or combinations thereof. More specifically, cottongauze is useful with the silver compositions of the present invention.For certain embodiments it is desirable to use a permeable (e.g., withrespect to moisture vapor), open apertured substrate (i.e., a scrim).For certain embodiments, the substrate may be a hydrocolloid, such as ahydrophilic polymer, or hydrophobic polymer matrix containinghydrophilic particles, as described in U.S. Pat. App. Pub. Nos.2004/0180093 and 2005/0124724.

The substrates (i.e., backings) are preferably porous to allow thepassage of wound fluids, moisture vapor, and air. In certainembodiments, the substrates are substantially impervious to liquid,especially wound exudate. In certain embodiments, the substrates arecapable of absorbing liquid, especially wound exudate. In certainembodiments, the substrate is an apertured liquid permeable substrate.

Suitable porous substrates include knits, wovens (e.g., cheese cloth andgauze), nonwovens (including spun-bonded nonwovens, and BMF (blown microfibers), extruded porous sheets, and perforated sheets. The apertures(i.e., openings) in the porous substrates are of sufficient size andsufficient number to facilitate high breathability. For certainembodiments, the porous substrates have at least 1 aperture per squarecentimeter. For certain embodiments, the porous substrates have nogreater than 225 apertures per square centimeter. For certainembodiments, the apertures have an average opening size (i.e., thelargest dimension of the opening) of at least 0.1 millimeter (mm). Forcertain embodiments, the apertures have an average opening size (i.e.,the largest dimension of the opening) of no greater than 0.5 centimeter(cm).

For certain embodiments, the porous substrates have a basis weight of atleast 5 grams/meter². For certain embodiments, the porous substrateshave a basis weight of no greater than 1000 grams/meter², and in someembodiments no greater than 200 grams/meter².

The porous substrates (i.e., backings) are preferably flexible yetresistant to tearing. For certain embodiments, the thickness of theporous substrates is at least 0.0125 millimeter (mm). For certainembodiments, the thickness of the porous substrates is no greater than15 mm, and for certain embodiments no greater than 3 mm.

Materials of the backing or support substrate include a wide variety ofmaterials including paper, natural or synthetic fibers, threads andyarns made from materials such as cotton, rayon, wool, hemp, jute,nylon, polyesters, polyacetates, polyacrylics, alginates,etbylene-propylene-diene rubbers, natural rubber, polyesters,polyisobutylenes, polyolefins (e.g., polypropylene polyethylene,ethylene propylene copolymers, and ethylene butylene copolymers),polyurethanes (including polyurethane foams), vinyls includingpolyvinylchloride and ethylene-vinyl acetate, polyamides, polystyrenes,fiberglass, ceramic fibers, and/or combinations thereof.

The backing can also be provided with stretch-release properties.Stretch-release refers to the property of an adhesive articlecharacterized in that, when the article is pulled from a surface, thearticle detaches from the surface without leaving significant visibleresidue. For example, a film backing can be formed from a highlyextensible and highly elastic composition that includes elastomeric andthermoplastic A-B-A block copolymers, having a low rubber modulus, alengthwise elongation to break of at least 200%, and a 50% rubbermodulus of not above 2,000 pounds/square inch (13.8 megapascals (MPa)).Such backings are described in U.S. Pat. No. 4,024,312 (Korpman).Alternatively, the backing can be highly extensible and substantiallynon-recoverable such as those described in U.S. Pat. No. 5,516,581(Kreckel et al,).

In certain embodiments, the coated substrates of the present inventionare nonadherent, although it should be understood that an adhesive(e.g., a pressure sensitive adhesive) could be added to an articlecoated with the solution. As used herein, the silver compositions of thepresent invention when coated on a substrate do not adhere significantlyto wound tissue such that they do not cause pain and/or destruction ofthe wound tissue upon removal and display a 180° peel strength of lessthan 1 N/cm from steel, as described in U.S. Pat. App. Pub. No.2005/0123590.

In certain embodiments, substrates coated with the silver compositioncan be covered on one or both sides by a permeable nonadherent outsidelayer to reduce adhesion and attachment to the wound. The nonadherentlayer can be attached to the substrate, such as by coating orlaminating. Alternatively, the coated substrate can be enclosed within anonadherent layer, such as sleeve. The nonadherent layer can be madefrom nonadherent woven or nonwoven fabrics such as nylon orperflourinated-material coatings on cotton gauze. The nonadherent layerprevents attachment of materials from the enclosed silver coatedsubstrate. At the same time, the nonadherent layer does not adverselyaffect the sustained release of silver from the coated substrate.

In another embodiment, the backing or support substrate can be composedof nonadherent material. For example, a nonadherent hydrophilic polymercan be used as the backing or support material, or coated on a permeableporous substrate, as described in U.S. Pat. Pub. Nos. 2004/0180093,2005/0123590, and 2005/0124724.

If desired, the coated substrate can be covered with two protectivefilms (for example, thin polyester films). These films optionally mayinclude a nonstick treatment and can function to facilitate extractionfrom a package and in handling the article. If desired, the coatedsubstrate can be cut into individual compresses, of sizes suitable forthe use, packaged in sealed sachets, and sterilized.

Pressure sensitive adhesives used in medical articles can be used inarticles of the present invention. That is, a pressure sensitiveadhesive material could be applied to the article of this invention, forexample, around the periphery, to adhere the article to the skin.

EXAMPLES

Objects and advantages of this invention are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this invention. Unless otherwiseindicated, all parts and percentages are on a weight basis, all water isdistilled water, and all molecular weights are weight average molecularweight.

Test Protocols Volatile Organic Content

Volatile organic content (VOC) can be determined using ASTM D 2369-03.Three pouches were placed in a constant temperature, constant humidity(CTH) room (50% RH 23° C.) for 48 hours (hrs). Six samples were punchedout with an 8.9 cm by 8.9 cm die punch for each pouch material. Eachsample was weighed with a Mettler balance. Samples were placedpolyethylene-side-up on aluminum trays and put in a forced air oven at110±5° C. for 60 minutes (min). Samples were re-equilibrated in the CTHroom for 48 hours and then reweighed.

Color Change

Color change was evaluated by visual ranking under fluorescent lighting(Philips, F32T8/TL735, Universal/Hi-Vision, E4). Samples were comparedto color standards and given a rating based on that visual comparison.Color change was the difference in ratings obtained by subtracting theinitial rating from the rating after treatment. Positive ratingsrepresent a darkening in appearance and negative ratings represent alightening in appearance.

Samples having color ratings (1-10) of the silver coated cotton sampleswere also measured using a Minolta Chroma Meter (CR-300, manufactured byKonica Minolta Photo Imaging U.S.A., Inc., Mahwah, N.J.) and gave thefollowing results.

TABLE 1 Color Ratings and Measured Color CIE Tristimulus values Visualcolor rating X Y Z White standard 92.98 94.95 108.54 1 71.9 72.97 52.433 59.74 59.48 33.84 4 50.77 50.00 23.68 5 41.92 39.87 23.07 7 28.8826.82 18.78 8 26.90 24.81 17.22 10  26.4 24.88 19.42

Silver Measurements Total Silver

Silver content of dressing was measured using EPA Procedure, EPA 6010Bwith ICP-AES detection.

Dressing Silver Ion Release

Silver ion release from dressing after 30 minutes immersion in distilledwater was determined using an Ag ion selective electrode (Orion,available VWR International, Batavia, Ill.). Two 3.175 cm diameter discswere cut from the web, weighed, and placed in 98 milliliter (mL) ofdistilled water and 2 mL of 5M NaNO₃ was added to the amber bottle. Thebottle was capped with a TEFLON lined lid and placed on ajar roller.After 30 minutes an ion selective electrode and double junctionreference electrode were placed in the solution. The temperature was21.20° C. The voltage across the electrodes was measured. A standardcurve was determined by plotting log (silver ion concentration) versusmillivolts (mV) for two standards, 1 microgram (μg) Ag⁺/mL and 10 μgAg⁺/mL and using this curve to determine sample silver ion release byconverting mV to silver ion concentration.

Substrate Anion Content

Anion content of the substrates was made using the following procedure.Extraction: The samples were weighed into 50 mL polypropylene centrifugetubes, with 25 mL of 18 MΩ water pipetted. The samples were extractedfor 24 hours at room temperature, at which time the cotton was removed.The sample was analyzed in triplicate with triplicate blanks using IonChromotography(IC).

IC: Solutions were transferred to 0.7 mL autosampler vials. Next, one 30μL aliquot was injected from each autosampler vial into a DIONEX DX500ion chromatograph using an AS3500 autosampler. The DIONEX chromatographused a GP40 Gradient Pump and EG40 Eluent Generator to establish aneluent (gradient KOH 10-54 mM in 18MΩ water) flow rate of 1 mL perminute. A conductivity detector (ED40), self-regenerating suppressor andcolumns AS18 (analytical) and AG18 (guard) were used.

Concentration of extractable anions in units of parts per million (ppm,μg/g) were determined using standard solutions to calibrate the systemfor fluoride, acetate, formate, chloride, sulfate, bromide nitrate andphosphate.

Various substrates were evaluated for anion content before coating withsilver salts. The anion content was determined using ion chromatographyby the procedure described above gave the results in Table 2.

TABLE 2 Concentration of extractable anions in units of parts permillion (ppm, μg/g). Sample Fluoride Acetate Formate Chloride SulfateBromide Nitrate Phosphate Spuntech 2   31.3 32 588   124   1.2 11.8  NDCotton (±1)   (±0.3) (±2) (±6) (±2)   (±0.2) (±0.4) <10 ppm Unitika 0.9 5.7   11.5  6.9 11.0 3.4 9.7 ND Cotton- (±0.3) (±0.6)   (±0.3)  (±0.1(±2)   (±0.4) (±1.0) <10 ppm COTTOASE Example 1.7 11.7 42 44.5 30.8 4.25.9 ND 4 non- (±0.2) (±1.2) (±2)   (±0.6) (±0.9) (±0.8) (±0.7) <10 ppmwoven Nisshinbo  0.28 32   ND 42   23.8 0.9 13.5  22.9 Cotton  (±0.02)(±4)   <1 ppm (±3) (±0.7) (±0.2) (±3.6) (±0.2)

TABLE 3 MATERIALS DESIG- NATION DESCRIPTION SOURCE/ADDRESS P-1Non-peelable pouch Pheonix Top: Paper/LDPE (low density Healthcarepolyethylene)/aluminum/adhesive/ Products, LLC, LDPE Milwaukee, WIBottom: Paper/LDPE/aluminum/adhesive/ LDPE VOC content 166 mg/m² To-1Peelable Foil pouch Tolas Health Care Top: TPC-0765B Packaging,PET/LDPE/Foil/Ionomer Feasterville, PA Bottom: TPC-0760BPET/LDPE/Foil/LDPE/Peelable Sealant VOC content 23 mg/m² To-2Non-Peelable Pouch Tolas Health Care Polyester/LDPE/Foil/IonomerPackaging, Top: TPC-0765B Feasterville, PA PET/LDPE/Foil/Ionomer Bottom:TPC-0765B PET/LDPE/Foil/Ionomer VOC content 15 mg/m² Te-1 Peelable FoilPouch Technipaq; Top: PET/White Opaque PP/ manufactured by Foil/PETechnipaq Inc., Bottom: PET/White Opaque Crystal Lake, ILPP/Foil/Peelable PE VOC content 25 mg/m² Te-2 Non-Peelable Foil PouchTechnipaq; Top: PET/White Opaque PP/ manufactured by Foil/PE TechnipaqInc., Bottom: PET/White Opaque PP/ Crystal Lake, IL Foil/PE VOC content22 mg/m² V-1 Peelable Pouch VP Group, Top: Feuchtwangen,Paper/LDPE/aluminum/adhesive/ Germany LDPE Bottom:Paper/LDPE/aluminum/adhesive/ LDPE/Full Peel Coating VOC content 258mg/m² ACC Activated carbon canister SorbiCap; Multisorb Technologies,Inc. Buffalo, NY; part number 02- 01803BG02

Example 1 Silver Sulfate Coated High Anion Containing Cotton Substrate

A silver sulfate coating solution was made by mixing silver sulfate(Colonial Metals Inc., Elkton, Md.) and water to make a 0.1333 gram (gor gm) AgSO₄ per 100 grams water solution. Spunlaced 100% cotton web (50g/m²; 30.48 cm wide, manufactured by Spuntech Industries, UpperTiberius, Israel) was coated with a slot die. The pump speed was 316mL/min. The coated web was dried at 356° F. (180° C.). The oven lengthwas 15.24 meters (m). The web speed was 3.049 m/min. The dried web wasgolden yellow. It was rolled up and placed in a heat sealable foilpouch. There was 4.7 mg total silver per gram dressing (Method: EPA6010B using ICP-AES). Silver ion release was determined to be 4.2milligrams (mg) Ag⁺/g dressing by the method defined.

Dressings were die cut and placed into the various packaging materialsat a water activity=0.5 and the package heat sealed. The packaged silverdressings were electron beam irradiated at 30 kGy or gamma irradiated at38 kGy. The samples were stored at room temperature for 1 to 8 weeksbefore evaluating color change. Table 4 has the results of thoseevaluations.

TABLE 4 Color change of Example 1. Time after Treatment Pouch MaterialTreatment (weeks) P-1 Te-1 Te-2 To-1 To-2 E-beam 1 1* 0 1 0 0.5 E-beam 80.5* 1 1 0.5 1 Gamma 1 1* 1* 2 1 0.5 Gamma 8 2* 1* 2* 2* 2* *indicatesthat the post irradiation dressing was not homogenous in color due toeither streaks or edge whitening; pre-irradiation color = 4

Example 2 Silver Sulfate Coated Low Anion Containing Cotton Substrate

Example 2 dressing was made as in Example 1 except that the spunlaced100% cotton web was manufactured by Unitika Ltd., Osaka, Japan; underthe trade designation COTTOASE, 280 millimeters (mm) wide; grams persquare meter (50 gm/m²). This resulted in a dressing with 5.5 mg totalsilver per gram dressing (Method: EPA 6010B using ICP-AES) and a silverion release of 3.6 mg Ag⁺/g dressing was measured by the method in theTest Protocols. The dried dressing was yellow in color.

Dressings were die cut and placed into the various packaging materialsat a water activity=0.5 and the package heat sealed. The packaged silverdressings were electron beam irradiated at 30 kGy or gamma irradiated at38 kGy. The samples were stored at room temperature for 1 to 8 weeksbefore evaluating color change. Table 5 has the results of thoseevaluations.

TABLE 5 Color change of Example 2. Time after Treatment Pouch MaterialTreatment (weeks) P-1 Te-1 Te-2 To-1 To-2 E-beam 1 0* 0 0 0 0 E-beam 8−0.5* 0 0.5 0.5 0 Gamma 1 −0.5* 1 1* 2* 0* Gamma 8 −0.5* 2* 3* 1* 1**indicates that the post irradiation dressing was not homogenous incolor due to either streaks or edge whitening; pre-irradiation color =3.

Example 3 Silver Sulfate Coated Low Anion Containing Cotton Substrate

Example 3 dressing was prepared as in Example 2 except that the dryingtemperature was 175° F. (79° C.). The dried silver sulfate coated cottonwas white. There was 5.3 mg total silver per gram dressing (Method: EPA60101B using ICP-AES) and the dressing had a silver ion release of 3.5mg Ag⁺/g dressing measured by the method in the Test Protocol. Dressingswere die cut and placed into the various packaging materials at a wateractivity=0.5 and an activated carbon canister (ACC) insert was thenadded and the package heat sealed, packaging with dressing and withoutinsert were also prepared. The packaged silver dressings were electronbeam irradiated at 30 kGy or gamma irradiated at 38 kGy. The sampleswere stored at room temperature for 1 to 8 weeks before evaluating colorchange. The table shows the effect that the activated carbon present inthe packaging has on the white Example 3 dressing material in variouspackaging materials.

TABLE 6 Color change of Example 3. Time after Treatment Pouch MaterialTreatment Insert (weeks) P-1 Te-1 Te-2 To-1 To-2 E-beam None 1 2* 1.51.75 1 1.75 E-beam ACC 1 0.75* 0.5 0.5 0.5 0.5 E-beam None 8 2* 2 1.5 21 E-beam ACC 8 1* 0.5 0.5 1 0.5 Gamma None 1 3.5* 4* 5.75* 3 2.75 GammaACC 1 0.75* 1 0.75 0.75 0.75 Gamma None 8 4* 7* 6* 4* 3* Gamma ACC 8 1*0.5 1 1 0.5 *indicates that the post irradiation dressing was nothomogenous in color due to either streaks or edge whitening;pre-irradiation color = 0

Example 4 Silver Sulfate Coated Multi Component Non-Woven

Silver sulfate coated on substrate was prepared as in Example 1 exceptthat the web was a multicomponent web composed of TENCEL lyocellfiber/Type 254 CELBOND Bicomponent Fiber (PET/Copolyester, 2.0 denier):95/5. The TENCEL lyocell fiber was manufactured by Lenzing AG. The Type254 CELBOND Bicomponent Fiber was manufactured by Trevira, Spartanburg,S.C. There was 4.0 mg total silver per gram dressing (Method: EPA 6010Busing ICP-AES). The silver ion release was measured as 2.5 mg Ag⁺/gdressing by the test procedure described in the Test Protocol section.

The Example 4 dressings were not stable at 8 weeks in the P-1 packagingafter electron beam or gamma irradiation at a water activity of 0.5 orat a water activity near 1.

The Example 4 dressings were stable at 50% RH or 100% RH in the To-1packaging after electron beam.

Example 5

A silver sulfate coating solution was prepared by placing 0.289 g silversulfate and 200 g distilled water in a glass bottle and capping thebottle and shaking at room temperature overnight. The resulting silversulfate (approximately 1000 μg Ag/g) solution was coated on 100% cottonspunlaced non-woven mesh (COTTOASE, containing less than 20 ppmchloride) by transferring the solution by pipet to saturate the meshthat was contained in a polystyrene dish. Each piece of non-woven mesh(50 grams per square meter (gsm)) was treated with approximately 5.5 gof the solution on a 4.375 inch by 4.375 inch (11.11 cm×11.11 cm) pieceof mesh. Approximately one gram of coating solution dripped off of themesh before the mesh was suspended in the oven for drying. Someadditional solution dripped off the mesh in the oven (estimated at 1 g).The coated mesh was dried in a forced air oven (Memmert Universal Oven,available from Wisconsin Oven Company, East Troy, Wis.) by heating at170° C. for 12 minutes. The color of the samples after drying was goldenyellow. The samples were placed in a foil pouch (Tolas Health CarePackaging, TPC-0765B/TPC-0760B construction) after drying and maintainedat a relative humidity inside the pouch of less than 25%. Samples werealso sealed in the foil pouch after drying and then exposed to gammairradiation (32.9-33.5 kGy). The samples were removed from the pouchesfor color measurement at 2 and 29 days after irradiaton. Color CIEtristimulus values of the samples were measured using a Minolta ChromaMeter (CR-300, manufactured by Konica Minolta Photo Imaging U.S.A.,Inc., Mahwah, N.J.). The results are shown in Table 7.

TABLE 7 Color of Example 5. Gamma Days after Color of CIE TristimulusValues irradiated Irradiation Sample X Y Z No — golden yellow 50.6 49.4221.09 Yes 2 golden yellow 47.21 45.57 20.87 Yes 29 golden yellow 53.5353.89 28.78

Example 6

Samples were prepared in same way as Example 5, except substrate was100% cotton non-woven from Suntec Union, Japan (Nissinbo, AN20601050, 60gsm). The color of the samples was a uniform golden yellow. The resultsare shown in Table 8.

TABLE 8 Color of Example 6. Gamma Days after Color of CIE TristimulusValues irradiated irradiation Sample X Y Z No — golden yellow 42.6 41.316.48 Yes 2 golden yellow 45.08 44.29 19.35 Yes 29 golden yellow 38.2536.58 15.32

Example 7

Samples were prepared in the same way as Examples 5 and 6 and were thenmeasured for silver release into a solution of distilled water andsodium nitrate using a silver ion selective electrode (Orion, availableVWR International, Batavia, Ill.). Sodium nitrate is used as an ionicstrength adjustor. The release was measured as described in the TestProtocol Section. The results of these measurements are in Table 9.

TABLE 9 Silver Ion Release. Silver Release mg Ag+/g Example Gamma Daysafter Color of sample in 30 Number irradiated irradiation Sample minutes5 No — golden yellow 7.9 5 Yes 2 golden yellow 5.7 5 Yes 29 goldenyellow 6.6 6 No — golden yellow 4.1 6 Yes 2 golden yellow 4.0 6 Yes 29golden yellow 3.5

Example 8

A 40 gram/m² spunlaced 100% cotton non-woven substrate was dip coated ina continuous manner into an approximately saturated solution of silversulfate, squeezed to remove excess coating solution, and then dried atapproximately 175° C. The resulting coated substrate contained 6 mgtotal silver per gram substrate and was golden yellow in color.Four-inch by 8-inch (10 cm×20 cm) samples were cut from the coatedsubstrate, and then folded into 4-inch×4-inch (10 cm×10 cm) two-plysamples. These two-ply samples were then placed into porous packaging(5.75″×9.75″ (14.6 cm×24.8 cm) unprinted Chevron peel pouch; uncoatedTYVEK 1073B/TPF-0501A construction; Tolas Health Care Packaging,Feasterville, Pa.; containing a VOC content of less than 50 mg/m²), andthe package was heat sealed. Some of these packaged samples were thene-beam irradiated at 21.5-28.9 kGy by Steris Isomedix in Libertyville,Ill., and some of these packaged samples were not irradiated.

Three packaged samples (either e-beam irradiated or not) were thenplaced into a second non-porous package (custom made from Technipaq Inc.Crystal Lake, Ill.; zipper pouch with bottom gusset/unprinted;12.5-inch×10.5-inch×2.5-inch OD (31.8 cm×26.7 cm×6.4 cm); 60 ga BiaxOrientated Nylon/A/0.00035 Foil/A/3.5 mil (0.009 cm) Linear Low DensityPolyethylene construction) along with one 3.0 gram activatedcarbon/silica gel (50/50) absorbent sachet (Multisorb Technologies,Inc., Buffalo, N.Y.). After the addition of the packaged samples and theabsorbent sachet, the second non-porous package was heat sealed, andthen aged at room temperature.

The samples were removed from both pouches for color measurement atspecified aging times as described in Table 10. Color CIE tristimulusvalues of the samples were measured using a Minolta Chroma Meter(CR-300, manufactured by Konica Minolta Photo Imaging U.S.A., Inc.,Mahwah, N.J.). Results are shown in Table 10.

TABLE 10 Color of Example 8. E-beam Months of Color of CIE TristimulusValues irradiated Aging study Sample X Y Z No initial golden yellow57.72 57.58 36.63 No initial golden yellow 54.79 54.43 31.85 No initialgolden yellow 56.20 56.00 33.03 Yes initial golden yellow 52.16 51.4129.58 Yes initial golden yellow 58.23 58.10 35.88 Yes initial goldenyellow 56.14 55.85 32.53 No 3 golden yellow 54.65 54.24 32.58 No 3golden yellow 58.66 58.71 38.30 No 3 golden yellow 58.04 58.07 37.77 Yes3 golden yellow 56.27 55.99 35.65 Yes 3 golden yellow 59.11 59.10 35.92Yes 3 golden yellow 58.37 58.27 35.92

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. Variousmodifications and alterations to this invention will become apparent tothose skilled in the art without departing from the scope and spirit ofthis invention. It should be understood that this invention is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein and that such examples and embodiments arepresented by way of example only with the scope of the inventionintended to be limited only by the claims set forth herein as follows.

1. A method of making a packaged antimicrobial article, the methodcomprising: preparing a composition comprising silver sulfate; coatingthe silver sulfate composition on a substrate; drying the coatedsubstrate to form an antimicrobial article; placing the antimicrobialarticle in packaging material having a volatile organic content of nogreater than 100 mg per square meter; and sealing the packaging materialwith the antimicrobial article therein.
 2. The method of claim 1 furthercomprising irradiating the antimicrobial article after the packagingmaterial is sealed. 3-4. (canceled)
 5. The method of claim 1 wherein thesubstrate is a silver nitrate oxidizable substrate.
 6. The method ofclaim 5 wherein drying the coated substrate occurs at a temperature thatcauses the silver sulfate composition to develop a yellowish color dueto the formation of silver in the zero valence state, and furtherwherein the antimicrobial article is color stable after irradiation.7-12. (canceled)
 13. The method of claim 1 wherein the antimicrobialarticle is maintained in an environment of no more than 50% RH at roomtemperature. 14-16. (canceled)
 17. The method of claim 1 wherein thepackaging material has an oxygen permeability of less than 0.01 cubiccentimeter per 645 square centimeters per 24 hours and/or a moisturevapor transmission rate of less than 0.01 gram per 645 squarecentimeters per 24 hours.
 18. The method of claim 1 wherein thepackaging material comprises an inner pouch and an outer pouch, whereinthe inner pouch has a Gurley Hill porosity of less than 100 s/100 cc ofair, and the outer pouch has an oxygen permeability of less than 0.01cubic centimeter per 645 square centimeters per 24 hours and/or amoisture vapor transmission rate of less than 0.01 gram per 645 squarecentimeters per 24 hours.
 19. The method of claim 1 wherein the silversulfate composition further comprises silver compounds other than silversulfate.
 20. The method of claim 19 wherein the silver compounds areselected from the group consisting of silver oxide, silver nitrate,silver acetate, silver citrate, silver chloride, silver lactate, silverphosphate, silver stearate, silver thiocyanate, silver carbonate, silversaccharinate, silver anthranilate, silver benzoate, and combinationsthereof.
 21. (canceled)
 22. The method of claim 20 wherein silver in thezero-valent state comprises less than 20 wt % of the composition basedon the total weight of the silver compounds of the composition. 23-24.(canceled)
 25. A packaged antimicrobial article made by the method ofclaim
 1. 26. A packaged antimicrobial article, comprising: anantimicrobial article comprising a substrate coated with a silversulfate composition; and packaging having the antimicrobial articlesealed therein; wherein the packaging comprises material having avolatile organic content of no greater than 100 mg per square meter. 27.The packaged article of claim 26 wherein the silver compounds areselected from the group consisting of silver oxide, silver nitrate,silver acetate, silver citrate, silver chloride, silver lactate, silverphosphate, silver stearate, silver thiocyanate, silver carbonate, silversaccharinate, silver anthranilate, silver benzoate, and combinationsthereof.
 28. The packaged article of claim 26 wherein the dried coatedsubstrate further comprises silver metal in the zero-valent state andhas a yellowish color. 29-31. (canceled)
 32. The packaged article ofclaim 26 wherein the substrate is a silver nitrate oxidizable substrate.33. (canceled)
 34. The packaged article of claim 33 wherein thesubstrate comprises cotton. 35-43. (canceled)
 44. A method of whiteningat least a portion of an antimicrobial article, the method comprising:providing a packaged antimicrobial article having at least a portioncolored other than white, wherein the article comprises a substratecoated with a silver salt composition comprising at least a portion ofthe silver in the zero-valent state, and wherein the antimicrobialarticle is sealed within packaging comprising material having a volatileorganic content of greater than 100 mg per square meter; and irradiatingthe packaged antimicrobial article to whiten at least a portion of theantimicrobial article. 45-50. (canceled)